What is the ME Association doing about Rituximab? Statement 8 July 2013

lilpink that was from Jo Best? Sorry I am just looking where it was posted and assume that is the case. Is she writing on behalf of IiME? I presume so but you don't say and I can't seem to determine. I won't post Dr Shepherds reply here in full. The exchange is all on Facebook for all to see just look for the title 'MEA pledge £50,000 for UK Rituximab Trial' and scroll through all the comments. Facebook is such a pain in the arse.

Moving on. Do you think that IiME will meet with the other interested charities and get together round a table? I mean if others are able to pledge funds now we could reach that target a lot quicker than with public donations alone. Some research charities do for example have funds pending projects. Any thoughts?

This reply is going to have to be in haste because I still have a small mountain of other work to deal with today

To summarise the key sequence of events:

1 I was in contact with Professor Jo Edwards and his group at UCL back in 2011 taking some quite detailed advice on how Rituximab had been used to treat other conditions and asking whether the group at UCL might be interested in doing a Rituximab trial that would involve people with ME/CFS

2 I was also making contact with other UK researchers at exactly the same time, who had the necessary expertise and clinical contacts, and who might also be interested in developing a protocol and applying to the MEA Ramsay Research Fund for funding

3 We also made repeated website statements about the MEA Ramsay Research Fund being willing to consider research funding applications for a Rituximab trial

4 Unfortunately, nobody at the time decided to follow up these MEA offers to help fund a Rituximab trial with a formal grant application.

5 We have a lot of other research commitments and so our focus then moved away from Rituximab - but we continued to make website statements about funding being available

6 So full marks to Invest in ME for also getting in touch with Professor Edwards at what I presume is a later date and persuading him, and the UCL Clinical Trials Group, to get involved and to develop a trial protocol. I hope this is clear: Invest in ME should be congratulated for what they have done here.

7 As soon as this information was made public by Invest in ME the MEA once again made it clear that we had funds available to help fund a trial and (later on) that funds might also be made available to help with any preliminary work

8 I have obviously been in contact with Professor Edwards again. We have had a very useful and constructive discussion this week picking up some of the points from our previous contact.

9 I have placed all this information in the public domain - as has Professor Edwards

10 There is no question of the MEA wanting to compete on this or to now set up another clinical trial - we are simply making it clear that we have a substantial amount of research funding available (plus donations that are now coming in) that could help to get this work moving sooner rather than later

10 Before going on holiday I wrote to Invest in ME to suggest that it would be helpful to have a meeting to discuss how the MEA (and other ME/CFS charities) could be involved in a joint fundraising initiative. Neil Riley, has also been in contact with Invest in ME while I have been away. I would still like to set up such a meeting.

11 As I keep saying, £400,000 is an awful lot of money for one charity to raise and surely it would be helpful if there was an initiative aimed at some form of joint charity fundraising effort to get this study moving asop

Finally...

Yes, the MRC, like all complex organisations moves slowly, but I take the view that we must engage and work with the MRC

Yes, it did take far too long for the MRC Expert Group to establish a list of research priorities

But I still believe it was a very significant achievement for us (the Expert Group) to persuade the MRC to shift direction into biomedical research and to then to produce £1.5 million in ring fenced funding

And Professor Stephen Holgate has made a major contribution here - without him I do not believe this would have happened. So it really is about time he had some praise from the ME Community.

I'm not interested in any bickering. IiME have made it clear that they have been organising a trial, and fundraising, for which I am very grateful. And the MEA have made it clear that they have a pot of money which they will make available if the trial's protocol passes its peer review procedures, for which I'm also grateful. It's seems that, not only are they both working towards the same aim, but the MEA is more than happy with the arrangements of the trial so far. If Stephen Holgate can manage to get some MRC funding fast tracked, at any stage, then so much the better.

Two advantages of MRC part-funding come to mind:
(i) It would give the trial more status

(II) It would save a lot of research charity money that could be used for other research.

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Yes. This second point is something that is important. It's a lot of money we are talking about and our charities are not flush with cash - hence I suppose the small scale studies generally seen in the past.

Charities can't fund large scale medical trial to the tune of millions, so the MRC will have to get involved at some point if a large scale trial is ever to take place. Charity money is best used for seed money, IMO, to fund preliminary activities or small scale trials which are then used as proof of concept, or proof of safety, to apply for larger grants. I think it's questionable if private/charity money will stretch to the £400,000 needed for a 30 person trial, and some other funding may be required.

Maria Gjerpe repeatedly made the point that one of the main reasons that she believed her MEandYou campaign was so successful was that she made it fun and positive - something that people would enjoy joining in with, something with a big 'feelgood' factor. She never deviated from that.

I think we can really learn a lot from that. I want this trial to be funded, and quickly. Let's please not drive people away by conflict and criticism over issues that are infinitely less important than the trial getting funded. We need to encourage our charities to work together, to co-fund, and use their various contacts and networks and spheres of influence and get this thing funded, fast. Together, we're much, much stronger.

The charity Invest in ME has provided a truly remarkable opportunity to address one of the biggest medical scandals in history and to remove what in 2007 Alex Fergusson, Presiding Officer (Speaker) of the Scottish Parliament, referred to as “the cold grip of psychiatry” on myalgic encephalomyelitis (ME), which he said was “still far too deeply rooted in the world of ME” (http://www.meactionuk.org.uk/Defiance_of_Science.htm).

Now, however, despite the power and control of the psychiatric lobby, thanks to Invest in ME and the invaluable support of Jonathan Edwards, Emeritus Professor of Connective Tissue Medicine at University College, London, (world-renowned for his work in B cell immunology and as lead researcher in the clinical trials of rituximab for rheumatoid arthritis), the neuro-immune disease ME is at last about to enter the realm of mainstream medicine in the UK under the guidance of Professor Edwards himself.

Invest in ME are at the forefront of international biomedical research and have by sheer determination and effort managed to put things in place for a trial of rituximab to begin on ME patients in the UK. They recognise the urgency of the situation and know that many ME patients do not have the luxury of time. The charity already has the facilities in place, including suitably experienced researchers (Professor Jo Cambridge is now principal researcher at UCL, and the ME trial will involve the same team working under her that carried out the rituximab research in RA).

The Clinical Trials Unit at UCL is already working on the protocol, and Invest in ME have agreed with Professor Edwards that the protocol will be externally reviewed even though the UCL team will make sure it is cast-iron by their own internal reviewers.

Invest in ME have been told this trial could start relatively quickly if the charity had funds available. Such an opportunity must not be lost. However, this will not happen without substantial funding.

We therefore ask everyone who is able to do so to donate whatever they can afford, in order that the UK rituximab trial can get under way as quickly as possible whilst the excellent facilities and committed staff at UCL and the active support of Professor Edwards remain available, so that ME can finally be recognised as the devastating multi-system neuro-immune disease that it is and – most importantly -- so that sufferers may at last have some hope of alleviation of their suffering.

Invest in ME have assured us that all donations to the rituximab fund will sit in a separate account which is totally ring-fenced, and should the trial not proceed, the following statement on the IiME website will be honoured –

What Happens With These Funds If The Project Does Not Go Ahead:
If the rituximab project does not go ahead for some reason then the funds raised will be transferred to the IiME Biomedical Research Fund to fund other biomedical research projects which are attached to our proposal for an examination and research facility based in Norwich Research park in Norfolk, UK. These funds will only be used for biomedical research into ME.
- http://www.investinme.org/IIME Statement 1306-01-faq.htm

A UK trial of rituximab is essential to move ME out of the realm of psychiatric dogma and into the realm of medical reality.

lilpink - many thanks for posting - I think that deserves a new thread to get attention because it's not on the topic of what the MEA is doing - it's a good new call for action from Prof Hooper and Margaret Williams.

I appreciate the enthusiasm from Hooper and Williams, but I think we all need to be careful to also express caution, perhaps especially when fundraising. I don't want to bring negative energy to the issue, but I do suggest that we don't over-play expectations. We've all been here before: Massive expectations with no guaranteed outcome. And if it ends without the result we want, many people might understandably find it difficult to deal with. It might be the case that Rituximab doesn't lead us anywhere meaningful. But even if 10% of patients experience a dramatic recovery, the NHS probably wouldn't approve the drug, because of its safety profile and its expense. So we should perhaps prepare ourselves for a long and bumpy road.

Edit: I'm not suggesting that people shouldn't donate. I think it's a very important trial, and it has the potential to transform the field of ME. But I think that people should be aware that the results from Norway do not suggest that a majority of patients will experience dramatic improvements, as far a as I understand the results.

I appreciate the enthusiasm from Hooper and Williams, but I think we all need to be careful to also express caution, perhaps especially when fundraising. I don't want to bring negative energy to the issue, but I do suggest that we don't over-play expectations. We've all been here before: Massive expectations with no guaranteed outcome. And if it ends without the result we want, many people might understandably find it difficult to deal with. It might be the case that Rituximab doesn't lead us anywhere meaningful. But even if 10% of patients experience a dramatic recovery, the NHS probably wouldn't approve the drug, because of its safety profile and its expense. So we should perhaps prepare ourselves for a long and bumpy road.

Edit: I'm not suggesting that people shouldn't donate. I think it's a very important trial, and it has the potential to transform the field of ME. But I think that people should be aware that the results from Norway do not suggest that a majority of patients will experience dramatic improvements, as far a as I understand the results.

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I agree entirely - this trial needs doing to test whether the response is the same as has been shown in the Norway trials however they didn't show 100% improvement/recovery so while I expect some ok results from the trial we really need to wait and see before getting excited about this. Hopefully the results lead to more trials in different drugs/biomedical research

I appreciate the enthusiasm from Hooper and Williams, but I think we all need to be careful to also express caution, perhaps especially when fundraising. I don't want to bring negative energy to the issue, but I do suggest that we don't over-play expectations. We've all been here before: Massive expectations with no guaranteed outcome. And if it ends without the result we want, many people might understandably find it difficult to deal with. It might be the case that Rituximab doesn't lead us anywhere meaningful. But even if 10% of patients experience a dramatic recovery, the NHS probably wouldn't approve the drug, because of its safety profile and its expense. So we should perhaps prepare ourselves for a long and bumpy road.

Edit: I'm not suggesting that people shouldn't donate. I think it's a very important trial, and it has the potential to transform the field of ME. But I think that people should be aware that the results from Norway do not suggest that a majority of patients will experience dramatic improvements, as far a as I understand the results.

Click to expand...

Important not to underplay either, Bob!

I don't think we have been here before - well conducted, placebo-controlled RCT; better results in a follow-up building on the previous work, as has been stated publicly (though the detail is still embargoed) by Fluge & Mella at the IiME conference; 67% of patients getting moderate to major improvement (vs 15% controls, and if memory serves, the only two non-CCC-defined participants); many other charities acknowledging the plausibility of the hypothesis and wanting to do their own trials; some patients in full remission, which has held up for up to four years now for some. We haven't seen this.

The work is in its early stages and dosing and co-therapy (e.g. with Valcyte) is something that people are looking at. The percentage of patients getting major benefit is likely to increase (it sounds as though perhaps it already has).

By the time the NHS will be looking at this we'll have more data on who the drug works for and its safety and efficacy for ME. At that point, it will be time for patients to pile on and demand it, if we need to. People with rheumatoid arthritis and other conditions get Rituximab; our disease is no less disabling and with data behind us from RCTs we'll be well-placed to campaign if we need to. Personally, I expect the NHS to cough up.

And regardless of the scale of benefits, just confirming that an immune therapy works for some ME patients benefits us all - validates our disease as an immune disease, gets us social recognition, gets a better attitude from our doctors and opens the floodgates to more research.

There's every reason to feel excited about this, I think - and I think we have to keep these reasons in mind.

Edit: There are many errors in this post, so please don't rely on it (I won't delete it because it's part of the later discussions.) (Corrections are pointed out in the discussions below.)

I just had another look at Fluge and Mella's 2011 paper, to see if I'd interpreted it wrongly.
(I haven't seen the results of their unpublished latest study.)

When compared to the placebo group, 8 out of 15 (53%) extra patients responded to treatment. These were all defined as a 'major' response to treatment. The average response duration was 25 weeks.

However, I am unable to work out exactly what a 'major' response meant, as their primary outcome scale is an average of four other outcome scales, and I can't find how they calculated their scores.

A 'major' response was defined as a Fatigue score ≥4.5 for at least six consecutive weeks ("also demanding recordings of some fatigue symptoms as major improvement (value 6) during the response period"), but I can't find the Fatigue scores at baseline for comparison, and I can't work out what a Fatigue score of 4.5 actually means, in terms of function.

I don't fully understand the way results have been presented, but a brief calculation suggests to me that average SF-36 physical function scores increased as follows...

Or, if taking the placebo group into account the changes are as follows, for the treatment group:
Baseline = 34 points
change (increase) = 4 points as a result of placebo
End, after increase as a result of placebo = 38 points (when improvements as a result of placebo are added)change (increase) = 9 points as a result of treatment *
End = 47 points

* This compares with an increase of 9.4 points for GET in the PACE trial.

Edit: This isn't an appropriate comparison. See posts below for details.

(I might have got my calculations wrong)

There are 3 or 4 patients in full remission, as far as I understand (but I might have this wrong), and I thought there was talk about the effects not being long lasting in all the patients who experienced full remission (again, I might have this wrong). These are certainly promising results, but 3 out of 30 patients in full remission means that 90% (27 out of 30) of patients are potentially going to be disappointed.

Edit:
There are 3 or 4 patients in full remission, as far as I understand (but I might have this wrong). These are promising results.
But 3 out of 15 patients in full remission means that 80% (12 out of 15) of patients are potentially going to be disappointed.

I'm still trying to make sense of the paper, but if anyone can explain what I've not understood, then I'd be grateful.

I just had another look at Fluge and Mella's 2011 paper, to see if I'd interpreted it wrongly.
(I haven't seen the results of their unpublished latest study.)

When compared to the placebo group, 8 out of 15 (53%) extra patients responded to treatment. These were all defined as a 'major' response to treatment. The average response duration was 25 weeks.

However, I am unable to work out exactly what a 'major' response meant, as their primary outcome scale is an average of four other outcome scales, and I can't find how they calculated their scores.

A 'major' response was defined as a Fatigue score ≥4.5 for at least six consecutive weeks ("also demanding recordings of some fatigue symptoms as major improvement (value 6) during the response period"), but I can't find the Fatigue scores at baseline for comparison, and I can't work out what a Fatigue score of 4.5 actually means, in terms of function.

I don't fully understand the way results have been presented, but a brief calculation suggests to me that average SF-36 physical function scores increased as follows...

Or, if taking the placebo group into account the changes are as follows, for the treatment group:
Baseline = 34 points
change (increase) = 4 points as a result of placebo
End, after increase as a result of placebo = 38 points (when improvements as a result of placebo are added)change (increase) = 9 points as a result of treatment *
End = 47 points

* This compares with an increase of 9.4 points for GET in the PACE trial.

(I might have got my calculations wrong)

There are 3 or 4 patients in full remission, as far as I understand (but I might have this wrong), and I thought there was talk about the effects not being long lasting in all the patients who experienced full remission (again, I might have this wrong). These are certainly promising results, but 3 out of 30 patients in full remission means that 90% (27 out of 30) of patients are potentially going to be disappointed.

These are certainly promising results, but 3 out of 30 patients in full remission means that 90% (27 out of 30) of patients are potentially going to be disappointed.

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I don't have time to re-read the paper just now, Bob - someone else will have to pick this one up - but just wanted to say that I think you're setting the bar extremely high if you're saying that patients who don't get a full remission - full remission! - will be disappointed. Frankly, at this point, I'd be thrilled with an increase in function of ten percentage points. It would transform my life.

Thanks for raising these issues, though. If you've got these questions, others will and it will be useful to discuss it. I just think it's important not to get sucked into the mindset of 'it's not perfect so it's not good enough'. I understand, of course, the years of frustration that people have and our wish for a return to health. But getting there is going to be a series of research steps and this is a very important one to take.